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Eung-Ho Choi, Mao-Qiang Man, Pu Xu, Shujun Xin, Zhili Liu, Debra A

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Presentation on theme: "Eung-Ho Choi, Mao-Qiang Man, Pu Xu, Shujun Xin, Zhili Liu, Debra A"— Presentation transcript:

1 Stratum Corneum Acidification Is Impaired in Moderately Aged Human and Murine Skin 
Eung-Ho Choi, Mao-Qiang Man, Pu Xu, Shujun Xin, Zhili Liu, Debra A. Crumrine, Yan J. Jiang, Joachim W. Fluhr, Kenneth R. Feingold, Peter M. Elias, Theodora M. Mauro  Journal of Investigative Dermatology  Volume 127, Issue 12, Pages (December 2007) DOI: /sj.jid Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

2 Figure 1 SC pH is less acidic in moderately aged humans and mice. (a) Surface pH was measured in unperturbed skin, using a flat electrode (see Materials and Methods) from the volar forearms of moderately aged humans (51–80 years, mean age 55.6 years, n=55) versus young (postpubertal) humans (13–21 years, mean age 20.2 years, n=65, P<0.05). Although SC pH was slightly more acidic in males versus females of both age groups, (b) SC acidification was less effective in both genders with aging. (c) SC surface pH measured from flanks also was less acidic in moderately aged (12–15 months) versus young (2–3 months) male mice (n=4–5 mice in each group, P<0.05). Data are presented as the mean±SE. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

3 Figure 2 pH increases at all levels of moderately aged versus young SC. Skin biopsies were taken from three young (8–12 weeks) and three moderately aged (12–15 months) mice, and extracellular pH measured in unperturbed SC at increasing depths from the surface using two-photon microscopy and fluorescence lifetime imaging (see Materials and Methods). Data are presented as the mean±SE. A 0μm depth denotes SC surface, whereas 8μm is the depth of the SC–SG interface. *P<0.05. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

4 Figure 3 Barrier recovery is delayed in moderately aged epidermis, but normalized by reacidification. (a) Moderately aged (12–15 months) and young (Y) (8–12 weeks) hairless mice were treated with acetone to perturb the epidermal permeability barrier (transepidermal water loss >4mg (cm2/hour)); then LBA was applied to selected young (YLBA) or aged (ALBA) animals to acidify the SC. Vehicle-treated mice served as controls. Barrier recovery consistently lagged in moderately aged mice at 6hours (P=0.007) after barrier perturbation. Three hours after barrier perturbation, LBA improved barrier recovery in both aged (ALBA) and young (YLBA) SC compared to vehicle controls (Y and A vehicle) confirming that neither group of animals can acidify its SC effectively at this time point (Hachem et al., 2005a). There was no difference in barrier recovery at 3hours in aged versus young vehicle-treated mice. In contrast, exogenous acidity improved barrier recovery in aged SC at 6hours, implying that moderately aged SC cannot effectively reacidify its SC by this time point. Thus, exogenous acidification normalizes permeability barrier homeostasis in moderately aged SC. Because both young and aged SCs recover by 24hours, it is likely that the barrier defect in moderately aged SC can be attributed to a delay in, rather than an absence of, SC acidification. Data are presented as the mean±SE. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

5 Figure 4 Epidermal lipid synthesis is normal in moderately aged mice. RNA was isolated from untreated epidermis from flanks of three moderately aged and three young mice. ACC and FAS levels were measured by quantitative PCR. Data are presented as the mean±SE. No statistically significant difference was found between ACC or FAS synthesis in moderately aged versus young mice. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

6 Figure 5 Abnormal lipid processing in moderately aged SC is reversed by reacidification. Moderately aged hairless mice were treated with acetone to perturb their epidermal barrier. Biopsies were obtained 6hours after treatment, and analyzed with electron microscopy, using ruthenium tetroxide postfixation to visualize processing of lipid into bilayers. (a) Untreated normal skin of young mice shows normal appearance of SC intercellular lamellar structures. (b) Control moderately aged animals treated with vehicle display abnormal, poorly processed lipid (black arrows). (c) LBA acidification treatment, however, normalizes lipid processing into competent lipid bilayers (white arrows) in moderately aged SC. Bar=0.2μm. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

7 Figure 6 Decreased β-GlcCer’ase activity alone accounts for abnormal lipid processing in moderately aged epidermis. Unperturbed moderately aged and young mouse skin was assayed with enzyme zymography for β-GlcCer’ase (see Materials and Methods). (a) Young SC treated with vehicle (control) displayed robust β-GlcCer’ase activity (green staining), which was mildly increased after (c) exogenous acidification. In contrast, β-GlcCer’ase activity was almost absent in (b) control aged SC, but was increased after (d) LBA pretreatment, suggesting that β-GlcCer’ase amounts are not substantially decreased in aged SC, because comparable activity is seen after exogenous acidification. The same exposure time was used for both moderately aged and young skin samples, so that relative fluorescence intensity is a true measure of relative enzyme activity. Bar=50μm. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

8 Figure 7 SC integrity is abnormal in moderately aged SC. Moderately aged (12–15 months) and young (8–12 weeks) hairless mice were treated with sequential D-squame strippings to perturb the SC, and transepidermal water loss was measured after each stripping as a measure of integrity. After five D-squame strippings, SC integrity was severely compromised in moderately aged SC, whereas damage to SC integrity in young SC was minimal. Data are presented as the mean±SE. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

9 Figure 8 Premature degradation of CDs in moderately aged murine SC is reversed by reacidification. (a and b) Whereas CDs (solid arrows) are largely intact one layer up into SC in (b) young mouse epidermis, CDs appear to be disintegrating prematurely (open arrows) at the same level in (a) moderately aged mouse epidermis. After topical treatment with the polyhydroxyl acid, LBA and CDs (arrowheads) reappear in (c) SC of moderately aged mice. Osmium tetroxide post-fixation; bar=0.5μm. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

10 Figure 9 Serine protease activity increases in moderately aged murine epidermis. Serine protease (SP) activity was compared in unperturbed (a) moderately aged and (b) young SC by enzyme zymography. The exposure times are same in both samples. (b) Young SC, treated with vehicle alone, displayed little SP activity (green), compared with (a) moderately aged SC treated with vehicle alone. Increased SP activity in aged SC is likely the result of increased acidity, rather than altered enzyme protein levels, because activity in young SC increases to match aged SC, when the pH of young SC is raised to levels comparable to aged skin with a topical superbase; (c) tetramethylguanidine. Bar=20μm. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

11 Figure 10 NHE1 expression is decreased in moderately aged versus young murine epidermis. NHE1 expression was assessed with immunohistochemistry, using an antibody specific for NHE1 (see Materials and Methods). Dotted lines indicate the SG/SC border. Arrows denote SG keratinocyte nuclei surrounded by plasma membranes that stain positively for NHE1. (a) NHE1 staining (green) in normal young skin was expressed most abundantly in the SG, with less staining in the basal layer and stratum spinosum. (b) Substantially less NHE1 protein is expressed in moderately aged epidermis. (c) Negative control staining in which the primary antibody was omitted demonstrated only background staining. Epidermal keratinocyte nuclei are counterstained with propidium idodide (red). Bar=20μm. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

12 Figure 11 Proposed pathways leading to abnormal function in moderately aged epidermis. Journal of Investigative Dermatology  , DOI: ( /sj.jid ) Copyright © 2007 The Society for Investigative Dermatology, Inc Terms and Conditions

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